tbuckley/cabot-search huggingface dataset:
Hyperoxemia in invasively ventilated COVID–19 patients–Insights from the PRoVENT–COVID study
Authors: A.M. Tsonas, D.M. van Meenen, M. Botta, G.S. Shrestha, O. Roca, F. Paulus, A.S. Neto, M.J. Schultz
Journal: Pulmonology (2022)

We determined the prevalences of hyperoxemia and excessive oxygen use, and the epidemiology, ventilation characteristics and outcomes associated with hyperoxemia in invasively ventilated patients with coronavirus disease 2019 (COVID–19). Post hoc analysis of a national, multicentre, observational study in 22 ICUs. Patients were classified in the first two days of invasive ventilation as 'hyperoxemic' or 'normoxemic'. The co–primary endpoints were prevalence of hyperoxemia (PaO2 > 90 mmHg) and prevalence of excessive oxygen use (FiO2 ≥ 60% while PaO2 > 90 mmHg or SpO2 > 92%). Secondary endpoints included ventilator settings and ventilation parameters, duration of ventilation, length of stay (LOS) in ICU and hospital, and mortality in ICU, hospital, and at day 28 and 90. We used propensity matching to control for observed confounding factors that may influence endpoints. Of 851 COVID–19 patients, 225 (26.4%) were classified as hyperoxemic. Excessive oxygen use occurred in 385 (45.2%) patients. Acute respiratory distress syndrome (ARDS) severity was lowest in hyperoxemic patients. Hyperoxemic patients were ventilated with higher positive end–expiratory pressure (PEEP), while rescue therapies for hypoxemia were applied more often in normoxemic patients. Neither in the unmatched nor in the matched analysis were there differences between hyperoxemic and normoxemic patients with regard to any of the clinical outcomes. In this cohort of invasively ventilated COVID–19 patients, hyperoxemia occurred often and so did excessive oxygen use. The main differences between hyperoxemic and normoxemic patients were ARDS severity and use of PEEP. Clinical outcomes were not different between hyperoxemic and normoxemic patients.
Abstract 13436: A Novel CETP Inhibitor, K-312, Suppresses PCSK9 Expression Through the Modulation of Its Promoter Activity
Authors: Katsutoshi Miyosawa, Yuichiro Watanabe, Takeshi Murakami, Dhruv Desai, Jiro Matsumoto, Sohei Tanabe, Masanori Aikawa
Journal: Circulation (2012)

Background:  Inhibition of proprotein convertase subtilisin/ kexin 9 (PCSK9) reduces LDL cholesterol levels. Although RNA and antibody therapeutics against PCSK9 are available, no small molecule inhibitors have been reported. A synthetic compound K-312, developed by us as a novel cholesteryl ester transfer protein (CETP) inhibitor, raises HDL- and lowers LDL-cholesterol levels in animals. We found that K-312 also suppresses PCSK9 expression in hepatocytes. We have explored the underlying mechanism for this effect.   Methods and Results:  K-312 decreased PCSK9 mRNA expression by >90% in the human hepatocyte cell line HepG2. K-312 did not affect stability of PCSK9 mRNA as examined via actinomycin D treatment, suggesting its effects on transcriptional regulation. Luciferase assay on deletion mutants of the PCSK9 promoter revealed that K-312 (3 µM, 24 hours) suppressed its transcriptional activity up to 52% by targeting the region within 450 bp upstream of the translation start site, where sterol-regulatory element (SRE), and hepatocyte nuclear factor 1 (HNF1) and histone nuclear factor P (HINFP) binding sites exist. Each site binds to SREBP1/2, HNF1α/β and HINFP, respectively. Mutation of SRE, HNF1 or HINFP binding site diminished suppressive effects of PCSK9 promoter activity by K-312, suggesting the role of these sites. As the binding sites for SREBP1/2, HNF1α/β and HINFP on the PCSK9 promoter are located closely, K-312 may interfere with the interaction between these transcription factors. K-312 (3 µM) also decreased mRNA expression levels of SREBP1 and 2 by 57% and 27%, respectively, but not HNF1α,HNF1β or HINFP. In addition, K-312 treatment decreased the active form of SREBP1. To further examine the effect of K-312 on the binding of SREBPs to SRE, we performed transcription factor binding assay using immobilized human PCSK9 SRE oligo DNA. We found that the addition of K-312 in the binding reaction inhibited binding of SREBP1 or 2 to SRE.   Conclusions:  Our findings suggest that the CETP inhibitor K-312 has a unique mechanism of action on suppression of PCSK9 transcription in part by inhibiting SREBP binding to SRE on the PCSK9 promoter and suppressing SREBP expression. K-312 may decrease LDL cholesterol levels through the inhibition of both CETP and PCSK9.
Regulated extravascular microenvironment via reversible thermosensitive hydrogel for inhibiting calcium influx and vasospasm
Authors: Binfan Zhao, Yaping Zhuang, Zhimo Liu, Jiayi Mao, Shutong Qian, Qiuyu Zhao, Bolun Lu, Xiyuan Mao, Liucheng Zhang, Yuguang Zhang, Wenguo Cui, Xiaoming Sun
Journal: Bioactive Materials (2022)

Arterial vasospasm after microsurgery can cause severe obstruction of blood flow manifested as low tissue temperature, leading to tissue necrosis. The timely discovery and synchronized treatment become pivotal. In this study, a reversible, intelligent, responsive thermosensitive hydrogel system is constructed employing both the gel–sol transition and the sol–gel transition. The "reversible thermosensitive (RTS)" hydrogel loaded with verapamil hydrochloride is designed to dynamically and continuously regulate the extravascular microenvironment by inhibiting extracellular calcium influx. After accurate implantation and following in situ gelation, the RTS hydrogel reverses to the sol state causing massive drug release to inhibit vasospasm when the tissue temperature drops to the predetermined transition temperature. Subsequent restoration of the blood supply alleviates further tissue injury. Before the temperature drops, the RTS hydrogel maintains the gel state as a sustained-release reservoir to prevent vasospasm. The inhibition of calcium influx and vasospasm in vitro and in vivo is demonstrated using vascular smooth muscle cells, mice mesenteric arterial rings, and vascular ultrasonic Doppler detection. Subsequent animal experiments demonstrate that RTS hydrogel can promote tissue survival and alleviate tissue injury responding to temperature change. Therefore, this RTS hydrogel holds therapeutic potential for diseases requiring timely detection of temperature change.
Metabolism and Activation of 1,1-Dimethylhydrazine and Methylhydrazine, Two Products of Nitrosodimethylamine Reductive Biotransformation, in Rats&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Journal: JNCI Journal of the National Cancer Institute (1983)

Nitrosodimethylamine (DMN) and two of its metabolites, methylhydrazine (MH) and 1,1-dimethylhydrazine (UDMH), were metabolized to CO2 by liver slices obtained from Sprague-Dawley rats. Under the conditions used, DMN and MH produced reactive metabolites that bound covalently to nucleic acids, but UDMH did not. Rat liver microsomes or 9,000xg supernatants were able to transform DMN, MH, and UDMH to CH2O. In the cases of MH and UDMH, enzymatic and nonenzymatic pathways of CH2O formation were observed in both liver microsomes and 9,000xg supernatants. DMN, MH, and UDMH led to covalent binding (CB) to proteins in incubation mixtures containing either microsomes or 9,000xg supernatants. In the case of DMN, the process was enzymatic and required NADPH in both cellular fractions. In the case of MH, the process was enzymatic in microsomes and required NADPH and O2 . With UDMH or MH and 9,000xg supernatants, nonenzymatic interactions resulting in CB to proteins dominated. All these results suggest that part of the CO2 produced during DMN metabolism might be derived from UDMH and MH. Similarly, a significant part of the CB of DMN metabolites to proteins in incubation mixtures containing microsomes or 9,000xg supernatants might be derived from enzymatic and nonenzymatic reactions of UDMH or MH. Also, a minor part of the CB of DMN-reactive metabolites to nucleic acids might have resulted from MH's further biotransformation to reactive metabolites. Overall, biotransformation of DMN and MH might not be a detoxication process, as previously thought, but one related to some of the DMN toxic effects.
Hodgkin lymphoma: 2023 update on diagnosis, risk‐stratification, and management
Authors: Stephen M. Ansell
Journal: American Journal of Hematology (2022)

Hodgkin lymphoma (HL) is an uncommon B-cell lymphoid malignancy affecting 8540 new patients annually and representing approximately 10% of all lymphomas in the United States.HL is composed of two distinct disease entities: classical HL and nodular lymphocyte-predominant HL. Nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte-rich HL are subgroups of classical HL.An accurate assessment of the stage of disease in patients with HL is critical for the selection of the appropriate therapy. Prognostic models that identify patients at low or high risk for recurrence, as well as the response to therapy as determined by positron emission tomography scan, are used to optimize therapy.Initial therapy for HL patients is based on the histology of the disease, the anatomical stage, and the presence of poor prognostic features. Patients with early-stage disease are typically treated with combined modality strategies utilizing abbreviated courses of combination chemotherapy followed by involved-field radiation therapy, while those with advanced-stage disease receive a longer course of chemotherapy, often without radiation therapy. However, newer agents, including brentuximab vedotin and anti-programmed death-1 (PD-1) antibodies, are now being incorporated into frontline therapy.High-dose chemotherapy (HDCT) followed by an autologous stem cell transplant (ASCT) is the standard of care for most patients who relapse following initial therapy. For patients who fail HDCT with ASCT, brentuximab vedotin, PD-1 blockade, non-myeloablative allogeneic transplant, or participation in a clinical trial should be considered.
33P Immune checkpoint inhibitor-induced cardiotoxicity is driven through inflammation, autophagy and stress
Authors: P. Efentakis, M. Gavriatopoulou, E. Choustoulaki, A. Georgoulis, G. Tsekenis, Z. Chakim, I. Ntanasis-Stathopoulos, M.A.C. Dimopoulos, E. Terpos, I. Andreadou
Journal: Annals of Oncology (2022)
18P Adoptive cell therapy (ACT) with bispecific gamma delta TCR+ invariant TCR+ NKT-like cells for multiple myeloma (MM): Comparison of preconditioning (PC) on outcome
Authors: T.A. Deisher, P. Jarzyna, S.H. Sawas, M. Pathak, S. Limasi
Journal: Annals of Oncology (2022)
27P Influence of single nucleotide polymorphisms (SNPs) in drug transporters ABCB1 and ABCG2 on intracerebral osimertinib efficacy in patients with non-small cell lung cancer
Authors: M.G.D. Veerman, R. Boosman, M. Jebbink, E. Oomen-de Hoop, A.J. van der Wekken, I. Bahce, L. Hendriks, C.M.J. Steendam, E. de Jonge, S.L. Koolen, R.H.N. van Schaik, E.F. Smit, A-M.C. Dingemans, A. Huitema, R.H. Mathijssen
Journal: Annals of Oncology (2022)
21P Circulating free and extracellular vesicles-derived microRNA as prognostic biomarkers in resected early-stage non-small cell lung cancer
Authors: P. Ulivi, L. Pasini, E. Petracci, M. Urbini, E. Felip, F. Stella, F. Davoli, M. Salvi, M. Beau-Faller, M. Tebaldi, I. Azzali, P. Solli, G. Lai, R. Amat, C. Carbonell, A. Martinez-Marti, E. Pencreach, A. Delmonte, L. Crinò
Journal: Annals of Oncology (2022)
34P Addition of oncolytic virus is as effective as addition of cytoreductive nephrectomy to the first-line treatment of anti-PD-1/anti-CTLA-4 antibodies in the murine metastatic renal cell carcinoma model
Authors: J.S. Park, W.S. Ham, M.E. Lee, W.S. Jang, K. Oh, N. Lee
Journal: Annals of Oncology (2022)
14P Sacubitril-valsartan increases pAMPK and reduces NLRP3, MyD88, interleukin-6 and galectin-3 in short-term doxorubicin-treated mice improving longitudinal strain and ejection fraction
Authors: A. Caronna, V. Quagliariello, S. Buccolo, F. Maurea, A. Luciano, A. Barbieri, G. Palma, A. Paccone, N. Maurea
Journal: Annals of Oncology (2022)
Cutaneous fungal infection masquerading as a gyrate erythema
Authors: Noah Kojima, Faysal Saab
Journal: BMJ (2022)

In the Western world, more than 90% of head and neck cancers are head and neck squamous cell carcinomas (HNSCCs). The most appropriate treatment approach for HNSCC varies with the disease stage and disease site in the head and neck. Concurrent chemoradiotherapy has become a widely used means for the definitive treatment of locoregionally advanced HNSCC. Although this multimodality treatment provides higher response rates than radiotherapy alone, the detection of residual viable tumor after the end of therapy remains an important issue and is one of the major applications of <sup>18</sup>F-FDG PET. Studies have shown that negative <sup>18</sup>F-FDG PET or PET/CT results after concurrent chemoradiotherapy have a high negative predictive value (&gt;95%), whereas the positive predictive value is only about 50%. However, when applied properly, FDG PET/CT can exclude residual disease in most patients, particularly patients with residual enlarged lymph nodes who would otherwise undergo neck dissection. In contrast to other malignancies, data are limited on the utility of <sup>18</sup>F-FDG PET for monitoring the response to induction chemotherapy in HNSCC or for assessing treatment response early during the course of definitive chemoradiotherapy. The proliferation marker <sup>18</sup>F-3′-deoxy-3′fluorothymidine is currently under study for this purpose. Beyond standard chemotherapy, newer treatment regimens in HNSCC take advantage of our improved understanding of tumor biology. Two molecules important in the progression of HNSCC are the epidermal growth factor receptor and the vascular endothelial growth factor (VEGF) and its receptor VEGF-R. Drugs attacking these molecules are now under study for HNSCC. PET probes have been developed for imaging the presence of these molecules in HNSCC and their inhibition by specific drug interaction; the relevance of these probes for response assessment in HNSCC will be discussed. Hypoxia is a common phenomenon in HNSCC and renders cancers resistant to chemo- and radiotherapy. Imaging and quantification of hypoxia with PET probes is under study and may become a prerequisite for overcoming chemo- and radioresistance using radiosensitizing drugs or hypoxia-directed irradiation techniques and for monitoring the response to these techniques in selected groups of patients. Although <sup>18</sup>F-FDG PET/CT will remain the major clinical tool for monitoring treatment in HNSCC, other PET probes may have a role in identifying patients who are likely to benefit from treatment strategies that include biologic agents such as epidermal growth factor receptor inhibitors or VEGF inhibitors.
A patient-driven clinicogenomic partnership for metastatic prostate cancer
Authors: Jett Crowdis, Sara Balch, Lauren Sterlin, Beena S. Thomas, Sabrina Y. Camp, Michael Dunphy, Elana Anastasio, Shahrayz Shah, Alyssa L. Damon, Rafael Ramos, Delia M. Sosa, Ilan K. Small, Brett N. Tomson, Colleen M. Nguyen, Mary McGillicuddy, Parker S. Chastain, Meng Xiao He, Alexander T.M. Cheung, Stephanie Wankowicz, Alok K. Tewari, Dewey Kim, Saud H. AlDubayan, Ayanah Dowdye, Benjamin Zola, Joel Nowak, Jan Manarite, Idola Henry Gunn, Bryce Olson, Eric S. Lander, Corrie A. Painter, Nikhil Wagle, Eliezer M. Van Allen
Journal: Cell Genomics (2022)

Molecular profiling studies have enabled discoveries for metastatic prostate cancer (MPC) but have predominantly occurred in academic medical institutions and involved non-representative patient populations. We established the Metastatic Prostate Cancer Project (MPCproject, mpcproject.org), a patient-partnered initiative to involve patients with MPC living anywhere in the US and Canada in molecular research. Here, we present results from our partnership with the first 706 MPCproject participants. While 41% of patient partners live in rural, physician-shortage, or medically underserved areas, the MPCproject has not yet achieved racial diversity, a disparity that demands new initiatives detailed herein. Among molecular data from 333 patient partners (572 samples), exome sequencing of 63 tumor and 19 cell-free DNA (cfDNA) samples recapitulated known findings in MPC, while inexpensive ultra-low-coverage sequencing of 318 cfDNA samples revealed clinically relevant AR amplifications. This study illustrates the power of a growing, longitudinal partnership with patients to generate a more representative understanding of MPC.
The relationship between chronic PTSD, cortical volumetry and white matter microstructure among Australian combat veterans
Authors: Madeline Romaniuk, Ying Xia, Gina Fisher, Kerstin Pannek, Jurgen Fripp, Justine Evans, Stephen Rose
Journal: Military Medical Research (2022)

Abstract Background Posttraumatic stress disorder (PTSD) has been associated with volumetric and white matter microstructural changes among general and veteran populations. However, regions implicated have greatly varied and often conflict between studies, potentially due to confounding comorbidities within samples. This study compared grey matter volume and white matter microstructure among Australian combat veterans with and without a lifetime diagnosis of PTSD, in a homogenous sample assessed for known confounding comorbidities. Methods Sixty-eight male trauma-exposed veterans (16 PTSD-diagnosed; mean age 69 years) completed a battery of psychometric assessments and underwent magnetic resonance and diffusion tensor imaging. Analyses included tract-based spatial statistics, voxel-wise analyses, diffusion connectome-based group-wise analysis, and volumetric analysis. Results Significantly smaller grey matter volumes were observed in the left prefrontal cortex ( P = 0.026), bilateral middle frontal gyrus ( P = 0.021), and left anterior insula ( P = 0.048) in the PTSD group compared to controls. Significant negative correlations were found between PTSD symptom severity and fractional anisotropy values in the left corticospinal tract ( R 2 = 0.34, P = 0.024) and left inferior cerebellar peduncle ( R 2 = 0.62, P = 0.016). No connectome-based differences in white matter properties were observed. Conclusions Findings from this study reinforce reports of white matter alterations, as indicated by reduced fractional anisotropy values, in relation to PTSD symptom severity, as well as patterns of reduced volume in the prefrontal cortex. These results contribute to the developing profile of neuroanatomical differences uniquely attributable to veterans who suffer from chronic PTSD.
Erratum to “Effect of Simulation-based Training on Surgical Proficiency and Patient Outcomes: A Randomised Controlled Clinical and Educational Trial” [Eur Urol 2022;81:385–393]
Authors: Abdullatif Aydın, Kamran Ahmed, Takashige Abe, Nicholas Raison, Mieke Van Hemelrijck, Hans Garmo, Hashim U. Ahmed, Furhan Mukhtar, Ahmed Al-Jabir, Oliver Brunckhorst, Nobuo Shinohara, Wei Zhu, Guohua Zeng, John P. Sfakianos, Mantu Gupta, Ashutosh Tewari, Ali Serdar Gözen, Jens Rassweiler, Andreas Skolarikos, Thomas Kunit, Thomas Knoll, Felix Moltzahn, George N. Thalmann, Andrea G. Lantz Powers, Ben H. Chew, Kemal Sarica, Muhammad Shamim Khan, Prokar Dasgupta, Umair Baig, Haleema Aya, Mohammed Husnain Iqbal, Francesca Kum, Matthew Bultitude, Jonathan Glass, Azhar Khan, Jonathan Makanjuola, John E. McCabe, Azi Samsuddin, Craig McIlhenny, James Brewin, Shashank Kulkarni, Sikandar Khwaja, Waliul Islam, Howard Marsh, Taher Bhat, Benjamin Thomas, Mark Cutress, Fadi Housami, Timothy Nedas, Timothy Bates, Rono Mukherjee, Stuart Graham, Matthieu Bordenave, Charles Coker, Shwan Ahmed, Andrew Symes, Robert Calvert, Ciaran Lynch, Ronan Long, Jacob M. Patterson, Nicholas J. Rukin, Shahid A. Khan, Ranan Dasgupta, Stephen Brown, Ben Grey, Waseem Mahmalji, Wayne Lam, Walter Scheitlin, Norbert Saelzler, Marcel Fiedler, Shuhei Ishikawa, Yoshihiro Sasaki, Ataru Sazawa, Yuichiro Shinno, Tango Mochizuki, Jan Peter Jessen, Roland Steiner, Gunnar Wendt-Nordahl, Nabil Atassi, Heiko Kohns, Ashley Cox, Ricardo Rendon, Joseph Lawen, Greg Bailly, Trevor Marsh
Journal: European Urology (2022)
Reply to Bernardo Rocco and Maria Chiara Sighinolfi’s Letter to the Editor re: James W.F. Catto, Pramit Khetrapal, Federico Ricciardi, et al. Effect of Robot-assisted Radical Cystectomy with Intracorporeal Urinary Diversion vs Open Radical Cystectomy on 90-Day Morbidity and Mortality Among Patients with Bladder Cancer: A Randomized Clinical Trial. JAMA 2022;327:2092–103
Authors: James W F Catto, Pramit Khetrapal, Gareth Ambler, Norman R Williams, Chris Brew-Graves, John D Kelly
Journal: European Urology (2022)
Ig Nobel prize 2022: it’s better to be lucky than smart, how heart rate reveals romantic feelings, and why ice cream works as cryotherapy
Authors: Janice Hopkins Tanne
Journal: BMJ (2022)

<h3>Objectives</h3> To investigate whether observational studies of HIV and herpes simplex virus type 2 (HSV-2) infections have the capacity to assess the HIV/HSV-2 epidemiological synergy. <h3>Methods</h3> An individual-based Monte Carlo model was used to simulate HIV/HSV-2 epidemics in two scenarios: no HIV/HSV-2 biological interaction and HSV-2 seropositivity enhancing HIV acquisition. Cross-sectional observational studies were simulated by sampling individuals from the population to assess resulting crude and adjusted ORs of the HIV/HSV-2 association. Meta-analyses were conducted to estimate the pooled mean ORs. Impact of under-reporting of sexual behaviour and miscapture of high-risk individuals was assessed through sensitivity analyses. <h3>Results</h3> Assuming no HIV/HSV-2 biological interaction, the crude HIV/HSV-2 OR ranged between 1.38 and 9.93, with a pooled mean of 6.45 (95% CI 5.81 to 7.17). Adjustment for the number of sexual partners over last year, over lifetime and for both partner numbers simultaneously reduced the mean OR to 5.45 (95% CI 4.90 to 6.06), 3.70 (95% CI 3.32 to 4.12) and 3.54 (95% CI 3.17 to 3.94), respectively. Assuming HIV/HSV-2 biological interaction, the crude OR ranged between 3.44 and 9.95, with a pooled mean of 8.05 (95% CI 7.14 to 9.07). The adjustments reduced the mean OR to 7.00 (95% CI 6.21 to 7.90), 3.76 (95% CI 3.32 to 4.25) and 3.68 (95% CI 3.25 to 4.17), respectively. Under-reporting of partners reduced the confounder-adjustment effects. Miscapture of high-risk individuals considerably lowered the estimated ORs. <h3>Conclusions</h3> It is difficult to control for sexual-behaviour confounding in observational studies. The observed HIV/HSV-2 association appears more consistent with two infections sharing the same mode of transmission, rather than with HSV-2 enhancing HIV acquisition.
[6]-Gingerol Suppresses Colon Cancer Growth by Targeting Leukotriene A4 Hydrolase
Authors: Chul-Ho Jeong, Ann M. Bode, Angelo Pugliese, Yong-Yeon Cho, Hong-Gyum Kim, Jung-Hyun Shim, Young-Jin Jeon, Honglin Li, Hualiang Jiang, Zigang Dong
Journal: Cancer Research (2009)

Abstract [6]-Gingerol, a natural component of ginger, exhibits anti-inflammatory and antitumorigenic activities. Despite its potential efficacy in cancer, the mechanism by which [6]-gingerol exerts its chemopreventive effects remains elusive. The leukotriene A4 hydrolase (LTA4H) protein is regarded as a relevant target for cancer therapy. Our in silico prediction using a reverse-docking approach revealed that LTA4H might be a potential target of [6]-gingerol. We supported our prediction by showing that [6]-gingerol suppresses anchorage-independent cancer cell growth by inhibiting LTA4H activity in HCT116 colorectal cancer cells. We showed that [6]-gingerol effectively suppressed tumor growth in vivo in nude mice, an effect that was mediated by inhibition of LTA4H activity. Collectively, these findings indicate a crucial role of LTA4H in cancer and also support the anticancer efficacy of [6]-gingerol targeting of LTA4H for the prevention of colorectal cancer. [Cancer Res 2009;69(13):5584–91]